Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
25 03 2023
25 03 2023
Historique:
received:
23
07
2022
accepted:
09
03
2023
medline:
28
3
2023
entrez:
25
3
2023
pubmed:
26
3
2023
Statut:
epublish
Résumé
AMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an opportunity for the development of selective therapeutics. AMPARs associated with TARP γ8 are enriched in the hippocampus, and are targets of emerging anti-epileptic drugs. To understand their therapeutic activity, we determined cryo-EM structures of the GluA1/2-γ8 receptor associated with three potent, chemically diverse ligands. We find that despite sharing a lipid-exposed and water-accessible binding pocket, drug action is differentially affected by binding-site mutants. Together with patch-clamp recordings and MD simulations we also demonstrate that ligand-triggered reorganisation of the AMPAR-TARP interface contributes to modulation. Unexpectedly, one ligand (JNJ-61432059) acts bifunctionally, negatively affecting GluA1 but exerting positive modulatory action on GluA2-containing AMPARs, in a TARP stoichiometry-dependent manner. These results further illuminate the action of TARPs, demonstrate the sensitive balance between positive and negative modulatory action, and provide a mechanistic platform for development of both positive and negative selective AMPAR modulators.
Identifiants
pubmed: 36966141
doi: 10.1038/s41467-023-37259-5
pii: 10.1038/s41467-023-37259-5
pmc: PMC10039940
doi:
Substances chimiques
TARP
0
Receptors, AMPA
0
Ligands
0
Calcium Channels
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1659Subventions
Organisme : NIMH NIH HHS
ID : R01 MH123474
Pays : United States
Organisme : NIMH NIH HHS
ID : R56 MH123474
Pays : United States
Organisme : Medical Research Council
ID : MRU105174197
Pays : United Kingdom
Informations de copyright
© 2023. The Author(s).
Références
Protein Sci. 2018 Jan;27(1):293-315
pubmed: 29067766
J Chem Phys. 2020 Jul 28;153(4):044130
pubmed: 32752662
ACS Med Chem Lett. 2019 Jan 23;10(3):228-236
pubmed: 30891118
J Physiol. 2021 Jan;599(2):397-416
pubmed: 32144935
Neuron. 2016 Sep 21;91(6):1305-1315
pubmed: 27618672
Nature. 2017 Sep 7;549(7670):60-65
pubmed: 28737760
J Pharmacol Exp Ther. 2019 Jun;369(3):345-363
pubmed: 30910921
Nat Commun. 2022 Feb 8;13(1):734
pubmed: 35136046
Elife. 2017 Aug 30;6:
pubmed: 28871958
J Mol Graph. 1996 Dec;14(6):354-60, 376
pubmed: 9195488
CNS Neurol Disord Drug Targets. 2008 Apr;7(2):129-43
pubmed: 18537642
Mol Pharmacol. 2022 May;101(5):343-356
pubmed: 35246481
Bioinformatics. 2013 Dec 15;29(24):3158-66
pubmed: 24078704
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):355-67
pubmed: 21460454
J Mol Graph. 1996 Feb;14(1):33-8, 27-8
pubmed: 8744570
Sci Rep. 2016 Jun 06;6:27459
pubmed: 27264908
J Physiol. 2021 Jan;599(2):453-469
pubmed: 32004381
J Gen Physiol. 2020 Apr 6;152(4):
pubmed: 32221541
J Mol Biol. 1993 Dec 5;234(3):779-815
pubmed: 8254673
J Struct Biol. 2016 Jan;193(1):1-12
pubmed: 26592709
J Comput Chem. 2010 Mar;31(4):671-90
pubmed: 19575467
J Cell Biol. 2003 May 26;161(4):805-16
pubmed: 12771129
Neuron. 2017 Dec 6;96(5):989-1001
pubmed: 29216460
Science. 2014 Apr 18;344(6181):304-7
pubmed: 24744376
Nat Med. 2016 Dec;22(12):1496-1501
pubmed: 27820603
Protein Sci. 2006 Nov;15(11):2507-24
pubmed: 17075131
ACS Med Chem Lett. 2018 Oct 16;10(3):237-242
pubmed: 30891119
Curr Opin Pharmacol. 2015 Feb;20:46-53
pubmed: 25462292
Nature. 2021 Jun;594(7863):448-453
pubmed: 33981040
Cell Rep. 2012 Jun 28;1(6):590-8
pubmed: 22813734
Neuron. 2017 May 3;94(3):569-580.e5
pubmed: 28472657
Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):777-81
pubmed: 8290599
Neuron. 2007 Sep 20;55(6):890-904
pubmed: 17880893
Bioinformatics. 2011 Jun 1;27(11):1575-7
pubmed: 21471012
J Comput Chem. 2008 Aug;29(11):1859-65
pubmed: 18351591
Science. 2019 Dec 6;366(6470):1259-1263
pubmed: 31806817
Curr Opin Pharmacol. 2004 Feb;4(1):4-11
pubmed: 15018832
Acta Neurol Scand Suppl. 2013;(197):19-24
pubmed: 23480152
Sci Rep. 2017 Apr 21;7(1):1050
pubmed: 28432359
Nat Rev Drug Discov. 2020 Dec;19(12):884-901
pubmed: 33177699
Nat Rev Drug Discov. 2021 Sep;20(9):710-722
pubmed: 34257432
J Neurosci. 2015 Dec 09;35(49):16171-9
pubmed: 26658868
Curr Opin Struct Biol. 2019 Aug;57:185-195
pubmed: 31185364
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
Acta Crystallogr D Struct Biol. 2019 Oct 1;75(Pt 10):861-877
pubmed: 31588918
Mol Pharmacol. 2019 Dec;96(6):835-850
pubmed: 31582576
Neuropharmacology. 2021 Oct 1;197:108709
pubmed: 34271020
J Pharmacol Exp Ther. 2014 Oct;351(1):124-33
pubmed: 25027316
Neuron. 2017 Mar 8;93(5):1126-1137.e4
pubmed: 28238551
J Biol Chem. 2020 Oct 23;295(43):14565-14577
pubmed: 32747446
Elife. 2018 Nov 09;7:
pubmed: 30412051
J Med Chem. 2016 May 26;59(10):4753-68
pubmed: 27067148
Neuron. 2014 Oct 01;84(1):41-54
pubmed: 25242221
Mol Cell. 2021 Dec 2;81(23):4771-4783.e7
pubmed: 34678168
J Pharmacol Exp Ther. 2016 May;357(2):394-414
pubmed: 26989142
Science. 2019 Apr 26;364(6438):
pubmed: 30872532
ACS Med Chem Lett. 2018 Dec 26;10(3):267-272
pubmed: 30891124
PLoS One. 2017 Mar 30;12(3):e0174742
pubmed: 28358902
Biochem Pharmacol. 2018 May;151:263-281
pubmed: 29330067
Neuron. 2017 May 17;94(4):713-730
pubmed: 28521126
Neuron. 2011 Apr 28;70(2):178-99
pubmed: 21521608
Nature. 2021 Nov;599(7884):325-329
pubmed: 34552241
J Chem Inf Model. 2011 Oct 24;51(10):2778-86
pubmed: 21919503
Nat Methods. 2017 Apr;14(4):331-332
pubmed: 28250466
Mol Pharmacol. 2020 May;97(5):336-350
pubmed: 32111699
Nature. 2009 Dec 10;462(7274):745-56
pubmed: 19946266
Nat Methods. 2017 Jan;14(1):71-73
pubmed: 27819658
Nature. 2021 Jun;594(7863):454-458
pubmed: 34079129
Cell. 2017 Sep 7;170(6):1234-1246.e14
pubmed: 28823560
Neuron. 2012 May 24;74(4):621-33
pubmed: 22632720
J Physiol. 2017 Oct 15;595(20):6517-6539
pubmed: 28815591
Pharmacol Rev. 2021 Oct;73(4):298-487
pubmed: 34753794